Since our discovery of the neural cell adhesion molecule, N-CAM, over 20 years ago, it has become clear that binding by cell adhesion molecules (CAMs) not only mediates cell-cell interactions, but also induces signals that affect embryonic development and adult physiology. In these proposed studies, we focus on the role of N-CAM in regulating critical cellular functions in the nervous system. Our first aim is designed to elucidate the events at and under the cell membrane by which N-CAM binding to the cell surface induces intracellular signals. The ability of N-CAM to induce the transcription factor NF-KB serves as the paradigm, but the studies will be extended to other N-CAM-mediated events. Recombinant proteins corresponding to various extracellular portions of N-CAM will be used to examine binding events, and site-directed mutagenesis of the N-CAM cytoplasmic region will be used to analyze intracellular events. In the second aim, the ability of N-CAM to induce the differentiation of neural stem cells into neurons by binding to heterophilic (non-N-CAM) receptors will be examined in terms of the mechanism of stimulation, the receptors involved, and the types of neurons induced by N-CAM binding. Multivalent recombinant proteins will be used to induce the response and be applied in conjunction with cells from our N-CAM knock-out mice to isolate heterophilic receptors. In the third aim, we will examine the role of N-CAM in inducing long term potentiation (LTP) of synapses, a key process underlying memory and learning. For these studies, synaptic dynamics and morphology will be compared in two strains of N-CAM knock-out mice, one with hippocampal LTP and one without LTP. A new method we have developed for identifying populations of active synapses will be used. The mechanisms defined by these studies should serve as exemplars for the activities of other CAMs. They should also yield new insights into how CAMs regulate gene expression, provide novel reagents for differentiating neural stem cells for potential clinical use, and expand our knowledge of the fundamental mechanisms that underlie memory and learning.